As a noninvasive method for measuring the concentration and distribution of chemicals in the living brain, MRS is an important tool for studying brain function and disorders. However, acquiring robust measurement of MRS signals requires a sophisticated study design and the successful implementation and maintenance of various MRS techniques. An active area for research area, MRS technology attracts major efforts from top research centers around the world. Clinical magnetic resonance imaging scanners that are optimized for performing structural and functional imaging studies also present daunting obstacles for MRS technical development. Most of the MRS protocols at NIH have been developed and implemented by the MRS Core under protocols 05-M-0144 (NCT00109174) and 11-M-0045 (NCT01266577). 1) Correction of baseline in short echo time proton MRS. Data acquisition at short echo time is needed to capture the entire metabolic profile of brain visible to proton MRS and to acquire, at the same time, the broad macromolecule baseline. The macromolecule baseline contributes to Cremer Rao Lower Bound of the metabolite signals. To accurately quantify this effect accurately in clinical short echo time MRS, we recently developed and optimized a method, based on mean squared error of the baseline, for determining the smoothness of baseline. This advance has led to a more objective and reliable determination of metabolite signals (Zhang et al., Magn Reson Med, 72(4):913-22. 2014 ). 2) Automatic correction of magnetic field inhomogeneity. It is essential to optimize the homogeneity of the magnetic field for all MRS experiments, because field inhomogeneity can easily destroy the critical separation of different chemicals. More importantly, an inhomogeneous field makes it difficult to effective suppress the tissue water signal effectively, making the reliable detection of more dilute chemicals impossible. This is particularly the case for anatomical regions of interest to psychiatric research. We optimized an automatic shimming method that consistently out-performs the automatic shimming methods provided by MRI scanner manufacturers. This new method has already greatly improved the quality of clinical MRS data acquired at NIH. 3) Multi-slice chemical shift imaging of N-acetylaspartate (NAA), creatine, and choline. The MRS core maintains a chemical shift imaging technique for mapping distribution of the neuronal marker N-acetylaspartate at 3 Tesla. This method simultaneously generates images of N-acetylaspartate, creatine, and choline-containing compounds. 4) Glutathione detection. Glutathione is a marker for oxidative stress. Many psychiatric and neurological disorders (such as schizophrenia, Alzheimer's disease, and stroke) are associated with abnormal glutathione levels. In collaboration with Steven Warach (NINDS) a glutathione editing method was developed on the Philip 3 Tesla scanner at the Suburban Hospital for studying stroke patients using adaptive line-fitting. We have also developed a single-shot method for measuring glutathione at 7 Tesla (Lally et al, J Magn Reson Imaging. 2016, 43(1):88-98.). 5) Carbon-13 MRS. Using carbon-13 labeled glucose or the glial-specific substrate acetate, it is possible to measure brain energetics and glutamate and glutamine cycling flux. Previously we invented a method for carbon-13 MRS by combining low power stochastic decoupling and intravenous infusion of glucose with a carbon-13 label at the C2 position. This strategy makes it possible to perform viable carbon-13 MRS on single channel clinicial MRI scanners. Using this strategy, we have acquired high quality carbon-13 MRS data from both the occipital and frontal lobes of healthy subjects and showed that it is possible to simultaneously detect two labeling pathways in the human brain. Recently, we have succeeded in implementing and optimizing this strategy on the 7 Tesla scanner with enhanced sensitivity and spectral resolution (Li et al, Magn Reson Med. 2016, 75(3):954-61), and we were the first to detect GABA turnover in the human brain. 6) Proton glutamate editing. Previously we implemented a single-voxel glutamate editing method with correction of eddy current effects for measuring glutamate concentration at 3 Tesla. A method for simultaneously extracting both glutamate and glutamine from multi-echo MRS data has also been developed and implemented (Zhang et al, Magn Reson Med. 2016, 76(3):725-32). Recently, We developed and optimized a new glutamate editing method that needs a single echo time to isolate the glutamate H4 signal at 7 Tesla. 7) GABA editing. Previously we implemented and refined a method for measuring GABA. As with N-acetylaspartate imaging, patient movements can lead to difficulty in the accurate determination of GABA. We used a navigator strategy, based on residual water, to track and correct for patient movement. We also developed spectral data processing software to correct for phase changes because of patient motion (van der Veen et al, NMR Biomed. 2017. doi: 10.1002/nbm.3725.). Improvements to these corrections have now been quantified and successfully applied in studies of human subjects. Currently, we are quantifying glutamate concentration using GABA-edited spectral data. The goal of this effort is to measure GABA and glutamate simultaneously. 8) NAAG editing. We successfully developed MRS methods for measuring the dipeptide neurotransmitter N-acetylaspartylglutamate (NAAG), which plays an important role in glutamate signaling. Our methods use regularized line-shape deconvolution, based on the L-curve method and Wiener filtering, to measure NAAG reliably (An et al, Magn Reson Med. 2014, 72(4):903-12). 9) 7 Tesla Phosphorus MRS imaging. We have developed a chemical shift imaging method for measuring phosphorus-containing chemicals in brain. The method has been successfully tested in occipital lobe. Development and testing for frontal lobe studies are currently in progress.